The statements in this section merely provide background information related to the present disclosure and may not constitute prior art.
Several lines of evidence suggest that Vitamin D plays a crucial role in myocardial function and metabolism. Studies performed in animals and cell culture have shown that Vitamin D3 and D5 and in particular the metabolically active form 1α25(OH)2D3 exerts direct effects on heart skeletal muscle Ca2+ metabolism, contractility and growth. Butriago, C., et al. Eur. J. Biochem. 269:2506-2515 (2002). Moreover, such effects were shown to be mediated through specific Vitamin D receptors (VDR). Simpson, R. U., et al. J. Biol. Chem. 260(15): 8882-8891. Biological activity of 1α25(OH)2D3 has been shown to proceed through two distinct pathways. The first characterized pathway involves signal mediated through nuclear Vitamin D receptor gene transcription. The second, more recently studied activity involves a rapid, non-genomic pathway that occurs within 30 minutes and is not reliant on RNA and protein synthesis. The exact non-genomic pathway involving Vitamin D3 in muscle and epithelial cells has not been exactly elucidated and is presently being extensively studied.
Several cardiac diseases are associated with dysfunctional cardiomyocyte structure and function. Two important conditions related to an improperly functioning heart include heart failure (HF) or cardiac hypertrophy and arrhythmias. HF is a leading cause of mortality in industrialized nations. Most patients with HF have a history of hypertension and/or left ventricular hypertrophy (LVH), and as a result these diseases are intimately linked. During the initial and middle stages of HF, the heart responds acutely to increased demand or overload by increasing the stroke volume and heart rate, which can raise cardiac output significantly over basal levels. Prolonged overload leads to cardiac remodeling which includes hypertrophy, loss of myocytes and increased interstitial fibrosis. Initially, these are adaptive changes which allow some normalized function by increasing the pumping capacity of the heart. Eventually, however, these compensatory mechanisms lead to reduced cardiac function and pathological symptoms become evident especially if the supply of oxygen or nutrients to the heart muscle is compromised. Increased muscle cell mass raises oxygen consumption and therefore predisposes the hypertrophic heart to ischemia. Furthermore, the heart is more susceptible to arrythmias, cardiac infarction, angina, chronic renal failure and ischemic and non-ischemic cardiomyopathy. The degree of remodeling progressively increases resulting in increased connective tissue formation concurrent with increasing cell mass, causing cardiac fibrosis. The increased stiffness of the left ventricular wall directly leads to diastolic HF.
Several other cardiac related conditions can manifest as a result of poor cardiac function due to cardiac overload and LVH including: arrythmias, cardiac infarction, angina, myocardial ischemia and cardiomyopathy. Despite studies and treatments for HF targeting the neurohormonal system and its cognate factors implicated in HF, there is a great need to understand the biology of the dysfunction and dysregulation of the cardiac myocyte itself. Many of these neurohormonal system factors have specific roles outside of the contractile cardiac myocyte itself, such as regulation of blood pressure and sodium retention, conditions that may affect the remodeling of the cardiomyocyte itself, albeit somewhat indirectly.
All of these findings demonstrate the importance of Vitamin D in progression of cardiac overload and the resultant diseases therefrom. The non-genomic pathway presents a convergence point for modulating cardiac output and cell contractility. To date, the exact pathways for regulating cardiomyocyte contraction via Vitamin D receptors have not been fully identified.
Gulbrandsen et al. (U.S. Pat. No. 5,700,790) reports a method for preventing myocardial failure in a mammal by administering an activated Vitamin D compound to produce a positive inotropic effect in the heart muscle. The vitamin D compounds used in Gulbrandsen et al. include, 1α-hydroxylated vitamin D2, D3 and D4 compounds. Gulbrandsen et al. rely on the ability of these Vitamin D compounds to increase the strength of the heart's contraction. However, the patent fails to show whether the administration of any Vitamin D compound changes the hemodynamic properties of any mammalian heart in vivo, including hearts that are under cardiac overload or hemodynamic stress, such as in a HF or a hypertensive subject. Moreover, Gulbrandsen et al. fails to describe methods for preventing the sequence of processes associated with the stages of compensatory heart failure morbidity that ultimately lead to decompensated heart failure mortality.
The present disclosure provides herein, the use of Vitamin D5 analogs acting upon Vitamin D receptors in the cardiomyocyte membrane and/or nucleus to relax the cardiomyocyte and thus ameliorate and prevent the remodeling process normally seen in cardiac overload diseases as a result of increased cardiac demand. As such, novel Vitamin D5 therapies and pharmaceutical compositions comprising Vitamin D5 compounds represent an excellent therapeutic avenue for treating cardiac overload and its related pathologies by directly treating the cardiomyocyte itself.